Human IgE+ B cells are derived from T cell-dependent and T cell-independent pathways
Human IgE+ B cells are derived from T cell-dependent and T cell-independent pathways
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DOI：
10.1016/j.jaci.2014.03.036
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发表时间：
2014-09-01
影响因子：
14.2
通讯作者：
van Zelm, Menno C.
中科院分区：
文献类型：
--
作者：
Berkowska, Magdalena A.;Heeringa, Jorn J.;van Zelm, Menno C.
目的：研究正常人和变态反应性疾病患者中表达IgE的B细胞的免疫生物学特性。方法：采用流式细胞术检测和纯化正常人、CD40配体缺陷患者和特应性皮炎患者中表达IgE的B细胞。结果：用多色流式细胞术检测到表达IgE的浆细胞和2个表达IgE的记忆B细胞亚群。这些表达IgE的细胞表现出抗原反应的分子和表型特征。免疫球蛋白E(+)浆细胞和CD2 7(+)免疫球蛋白(+)记忆B细胞的复制历史和SHM水平符合生发中心(GC)依赖的途径，通常通过免疫球蛋白G中间体，从S-S表观转换区的S伽马残留物中得到证明。CD27(-)IgE(+)细胞表现出有限的增殖和SHM，并存在于CD40配体缺陷的患者中，表明其来源不依赖于GC。与健康对照组和银屑病患者相比，特应性皮炎患者外周血中IgE(+)浆细胞和CD27(+)IgE(+)记忆B细胞数量正常，而具有高SHM负荷的CD27(-)IgE(+)记忆B细胞数量增加。结论：我们描述了健康人GC依赖和GC非依赖的IgE(+)B细胞反应，提示GC非依赖途径参与了人类IgE介导的疾病。这些发现为了解IgE介导的疾病的发病机制提供了新的见解，并可能有助于准确监测接受抗IgE治疗的重症患者的IgE(+)B细胞。
Background: The prevalence of IgE-mediated diseases has been increasing worldwide, yet IgE-expressing B cells are poorly characterized, mainly because of their scarcity and low membrane IgE levels.Objective: We sought to study the immunobiology of human IgE-expressing B cells in healthy subjects and patients with allergic disease.Methods: We used a stepwise approach for flow cytometric detection and purification of human IgE-expressing B cells in control subjects, CD40 ligand-deficient patients, and patients with atopic dermatitis. Molecular analysis of replication histories, somatic hypermutation (SHM), and immunoglobulin class-switching was performed.Results: Using multicolor flow cytometry, we reliably detected IgE-expressing plasma cells and 2 IgE-expressing memory B-cell subsets. These IgE-expressing cells showed molecular and phenotypic signs of antigen responses. The replication history and SHM levels of IgE(+) plasma cells and CD27(+)IgE(+) memory B cells fitted with a germinal center (GC)-dependent pathway, often through an IgG intermediate, as evidenced from S gamma remnants in S mu-S epsilon switch regions. CD27(-)IgE(+) cells showed limited proliferation and SHM and were present in CD40 ligand-deficient patients, indicating a GC-independent origin. Patients with atopic dermatitis had normal numbers of blood IgE(+) plasma cells and CD27(+)IgE(+) memory B cells but increased numbers of CD27(-)IgE(+) memory B cells with high SHM loads compared with those seen in healthy control subjects and patients with psoriasis.Conclusions: We delineated GC-dependent and GC-independent IgE(+) B-cell responses in healthy subjects and indicated involvement of the GC-independent pathway in a human IgE-mediated disease. These findings provide new insights into the pathogenesis of IgE-mediated diseases and might contribute to accurate monitoring of IgE(+) B cells in patients with severe disease undergoing anti-IgE treatment.